Schizophrenia acetylcholine

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Leonard, S., Gault, J., Hopkins, J. et al. Association of promoter variants in the alpha7 nicotinic acetylcholine receptor subunit gene with an inhibitory deficit found in schizophrenia. Arch. Gen. Psychiatry 59 1085-1096,2002. 

Traditionally, most affective disorders have been treated with compounds that resemble the neurotransmitters that are deficient or in excess in specific brain regions. The aberrant levels of neurotransmitters (or their receptors), such as norepinephrine, dopamine, acetylcholine, and serotonin, have correlated with behavioral symptoms of schizophrenia, depression, anxiety, sleep disorders, motor dysfunctions, attention difficulties, and cognitive disorders. Most drugs discovered for these disorders resulted from screening compounds directly in rodent behavioral models that mimic the behavior of the disease. In these cases, the molecular target" or mechanism of action was assumed to be the deficiency or excess of a neurotransmitter. 

Because cocaine and amphetamine psychoses are anything but psychedelic, they are instructive to examine in terms of our ncurobiological hypotheses about why some altered states are dreamlike and others are not. Although cocaine and amphetamines push the dopamine system to the break point, they do not so radically alter the REM sleep modulators, norepinephrine, serotonin, or acetylcholine. Thus, they create a quite different altered state, one more akin to schizophrenia than to dream delirium. 

Dopamine autoreceptors play a role in Parkinson s disease, schizophrenia and drug addiction. Dopamine heteroreceptors affecting the release of acetylcholine and of amino acid neurotransmitters in the basal ganglia are also relevant for Parkinson s disease. Peripheral dopamine heteroreceptors on postganglionic sympathetic terminals influence heart rate and vascular resistance through modulation of noradrenaline release. 

Sleep loss is therefore common in and contributes powerfully to the development of psychosis. In the case of schizophrenia (now thought to be a disorder of excessive dopamine release and/or heightened effectiveness of dopamine), we can hypothesize an indirect but positive interaction with the other modulators of the awake state, noradrenaline and serotonin, and a direct negative interaction with acetylcholine. Significantly for my dreaming-as-delirium thesis, no distinctive changes in sleep are seen in chronic schizophrenia. 

Postmortem expression of muscarinic acetylcholine receptors in schizophrenia... 

Different pharmacological agents with an effect on the mAChR system have been used in the treatment of schizophrenia. These include agents that affect the concentration of intrasynaptic acetylcholine as well as agonists and antagonists of mAChRs. 

Freedman R, Adams CE, Leonard S. 2000. The alpha7-nico-tinic acetylcholine receptor and the pathology of hippocampal intemeurons in schizophrenia. J Chem Neuroanat 20 299-306. 

Raedler TJ, Knable MB, Jones DW, Lafargue T, Urbina RA, et al. 2000. In vivo olanzapine occupancy of muscarinic acetylcholine receptors in patients with schizophrenia. Neuropsychopharmacology 23 56-68. 

Durany N, Zochling R, Boissl KW, Paulus W, Ransmayr G, et al. 2000. Human post-mortem striatal alpha4beta2 nicotinic acetylcholine receptor density in schizophrenia and Parkinson s syndrome. Neurosci Lett 287 109-112. 

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